Streptococcus pyogenes owes its major success as a pathogen
to
its ability to colonize and rapidly multiply and spread in its host
while
evading phagocytosis and confusing the immune system.

Acute diseases associated with Streptococcus pyogenes
occur chiefly in the respiratory tract, bloodstream, or
the
skin. Streptococcal disease is most often a respiratory infection
(pharyngitis
or tonsillitis) or a skin infection (pyoderma). Some strains of
streptococci
show a predilection for the respiratory tract; others, for the skin.
Generally,
streptococcal isolates from the pharynx and respiratory tract do not
cause
skin infections. Figure 3 describes the pathogenesis of S. pyogenes
infections.

S. pyogenes is the leading cause of uncomplicated bacterial pharyngitis
and tonsillitis commonly referred to a strep throat.
Other
respiratory infections include sinusitis,
otitis, and pneumonia.
Infections of the skin can be superficial (impetigo) or deep
(cellulitis). Invasive streptococci cause joint or bone
infections,
destructive wound infections (necrotizing fasciitis) and
myositis,
meningitis
and
endocarditis. Two post streptococcal sequelae,
rheumatic
fever and glomerulonephritis, may follow streptococcal
disease,
and occur in 1-3% of untreated infections. These conditions and their
pathology
are not attributable to dissemination of bacteria, but to aberrent
immunological
reactions to Group A streptococcal antigens.
Scarlet fever and streptococcal
toxic shock syndrome are systemic responses to circulating
bacterial
toxins.

The cell surface of Streptococcus pyogenes accounts
for
many of the bacterium's determinants of virulence, especially those
concerned
with colonization and evasion of phagocytosis and the host immune
responses.
The surface of Streptococcus pyogenes is incredibly complex and
chemically-diverse. Antigenic components include capsular
polysaccharide
(C-substance), cell wall peptidoglycan and lipoteichoic
acid
(LTA), and a variety of surface proteins, including M protein,
fimbrial
proteins, fibronectin-binding proteins, (e.g. Protein F)
and cell-bound streptokinase.

The cytoplasmic membrane of S. pyogenes contains some
antigens
similar to those of human cardiac, skeletal, and smooth muscle, heart
valve
fibroblasts, and neuronal tissues, resulting in molecular mimicry
and a tolerant or suppressed immune response by the host.

The cell envelope of a Group A streptococcus is illustrated in
Figure
2. The complexity of the surface can be seen in several of the electron
micrographs of the bacterium that accompany this article.

In Group A streptococci, the R and T proteins are
used
as epidemiologic markers and have no known role in virulence. The group
carbohydrate antigen (composed of N-acetylglucosamine and
rhamnose)
has been thought to have no role in virulence, but emerging strains
with
increased invasive capacity produce a very mucoid colony, suggesting a
role of the capsule in virulence.

The M proteins are clearly virulence factors associated with
both colonization and resistance to phagocytosis. More than 50
types
of S. pyogenes M proteins have been identified on the basis of
antigenic
specificity, and it is the M protein that is the major cause of
antigenic
shift and antigenic drift in the Group A streptococci. The M protein
(found
in fimbriae) also binds fibrinogen from serum and blocks the binding of
complement to the underlying peptidoglycan. This allows survival of the
organism by inhibiting phagocytosis.

The streptococcal M protein, as well as peptidoglycan,
N-acetylglucosamine,
and group-specific carbohydrate, contain antigenic epitopes that mimic
those of mammalian muscle and connective tissue. As mentioned above,
the
cell surface of recently emerging strains of streptococci is distinctly
mucoid (indicating that they are highly encapsulated). These strains
are
also rich in surface M protein. The M proteins of certain M-types are
considered
rheumatogenic
since they contain antigenic epitopes related to heart muscle, and they
therefore may lead to autoimmune rheumatic carditis (rheumatic fever)
following
an acute infection.

The Hyaluronic Acid Capsule

The capsule of S. pyogenes is non antigenic since it
is
composed of hyaluronic acid, which is chemically similar to
that
of host connective tissue. This allows the bacterium to hide its own
antigens
and to go unrecognized as antigenic by its host. The Hyaluronic acid
capsule
also prevents opsonized phagocytosis by neutrophils or mancrophages.

Adhesins

Colonization of tissues by S. pyogenes is thought to result
from
a failure in the constitutive defenses (normal flora and other
nonspecific
defense mechanisms) which allows establishment of the bacterium at a
portal
of entry (often the upper respiratory tract or the skin) where the
organism
multiplies and causes an inflammatory purulent lesion.

It is now realized that S. pyogenes (like many other
bacterial
pathogens) produces multiple adhesins with varied specificities. There
is evidence that Streptococcus pyogenes utilizes lipoteichoic
acids (LTA), M protein, and multiple fibronectin-binding
proteins in its repertoire of adhesins. LTA is anchored to proteins
on the bacterial surface, including the M protein. Both the M proteins
and lipoteichoic acid are supported externally to the cell wall on
fimbriae
and appear to mediate bacterial adherence to host epithelial
cells.
The fibronectin-binding protein, Protein F, has also been shown
to mediate streptococcal adherence to the amino terminus of fibronectin
on mucosal surfaces.

Identification of Streptococcuspyogenes adhesins has long
been
a subject of conflict and debate. Most of the debate was between
proponents
of the LTA model and those of the M protein model. In 1972, Gibbons and
his colleagues proposed that attachment of streptococci to the oral
mucosa
of mice is dependent on M protein. However, Olfek and Beachey argued
that
lipoteichoic acid (LTA), rather than M protein, was responsible for
streptococcal
adherence to buccal epithelial cells. In 1996, Hasty and Courtney
proposed
a two-step model of attachment that involved both M protein and
teichoic
acids. They suggested that LTA loosely tethers streptococci to
epithelial
cells, and then M protein and/or other fibronectin (Fn)-binding
proteins
secure a firmer, irreversible association. The first streptococcal
fibronectin-binding
protein (Sfb) was demonstrated in 1992. Shortly thereafter, protein F
was
discovered. Most recently (1998), the M1 and M3 proteins were
shown
to bind fibronectin.

Extracellular products: invasins and
exotoxins

Colonization of the upper respiratory tract and acute pharyngitis
may
spread to other portions of the upper or lower respiratory tracts
resulting
in infections of the middle ear (otitis media), sinuses (sinusitis), or
lungs (pneumonia). In addition, meningitis can occur by direct
extension
of infection from the middle ear or sinuses to the meninges or by way
of
bloodstream invasion from the pulmonary focus. Bacteremia can also
result
in infection of bones (osteomyelitis) or joints (arthritis). During
these
aspects of acute disease the streptococci bring into play a variety of
secretory proteins that mediate their invasion.

For the most part, streptococcal invasins and protein toxins
interact
with mammalian blood and tissue components in ways that kill host cells
and provoke a damaging inflammatory response. The soluble extracellular
growth products and toxins of Streptococcus pyogenes (see
Figure
2, above), have been studied intensely. Streptolysin S is an
oxygen-stable
leukocidin; Streptolysin O is an oxygen-labile leukocidin.
NADase
is also leukotoxic. Hyaluronidase (the original
"spreading
factor") can digest host connective tissue hyaluronic acid, as well as
the organism's own capsule. Streptokinases participate in
fibrin
lysis. Streptodornases A-D possess deoxyribonuclease activity;
Streptodornases
B and D possess ribonuclease activity as well. Protease
activity
similar to that in Staphylococcus aureus has been shown in
strains
causing soft tissue necrosis or toxic shock syndrome. This large
repertoire
of products is important in the pathogenesis of S. pyogenes
infections.
Even so, antibodies to these products are relatively insignificant in
protection
of the host.

The streptococcal invasins act in a variety of ways summarized in
Table
1 at the end of this article. Streptococcal invasins lyse eukaryotic
cells,
including red blood cells and phagocytes; they lyse other host
macromolecules,
including enzymes and informational molecules; they allow the bacteria
to spread among tissues by dissolving host fibrin and intercellular
ground
substances.

Pyrogenic Exotoxins

Three streptococcal pyrogenic exotoxins (SPE), formerly
known
as Erythrogenic toxin, are recognized: types A, B, C. These
toxins
act as superantigens by a mechanism similar to those described
for
staphylococci. As antigens, they do not requiring processing by antigen
presenting cells. Rather, they stimulate T cells by binding class II
MHC
molecules directly and nonspecifically. With superantigens about 20% of
T cells may be stimulated (vs 1/10,000 T cells stimulated by
conventional
antigens) resulting in massive detrimental cytokine release. SPE A and
SPE C are encoded by lysogenic phages; the gene for SPE B is located on
the bacterial chromosome.

The erythrogenic toxin is so-named for its association with scarlet
fever which occurs when the toxin is disseminated in the blood.
Re-emergence
in the late 1980's of exotoxin-producing strains of S. pyogenes
has been associated with a toxic shock-like syndrome similar in
pathogenesis and manifestation to staphylococcal toxic shock syndrome,
and with other forms of invasive disease associated with severe tissue
destruction. The latter condition is termed necrotizing fasciitis.
Outbreaks of sepsis, toxic shock and necrotizing fasciitis have been
reported
at increasing frequency. The destructive nature of wound infections
prompted
the popular press to refer to S. pyogenes as "flesh-eating
bacteria"
and "skin-eating streptococci". The increase in invasive
streptococcal
disease was associated with emergence of a highly virulent serotype
M1
which is disseminated world-wide. The M1 strain produces the
erythrogenic
toxin (Spe A), thought to be responsible for toxic shock, and the
enzyme cysteine protease which is involved in tissue destruction.
Because clusters of toxic shock were also associated with other
serotypes,
particularly M3 strains, it is believed that unidentified host factors
may also have played an important role in the resurgence of these
dangerous
infections.